Inflammation

• What is inflammation?
• Outcomes of early inflammation
• Causes of inflammation
• When to see a doctor
• Tests for inflammation
• Treatment of inflammation

What is inflammation?

Inflammation is described as having four major features:

• Redness
• Heat
• Pain
• Loss of Function

Inflammation is a completely natural process that is part of the body’s response to any injury that it undergoes. This could be a toxin, a chemical or an infection. Inflammation is designed to wall off the area so that damage cannot spread very far. It then tries to destroy the cause of the damage. Finally, inflammation is involved in healing the body and hopefully returning it to the exact state that it was in before the injury. There are two types of inflammation, acute inflammation which starts suddenly but goes away relatively quickly, and chronic inflammation that can remain active for months, years or decades. Inflammation is an integral part of the immune system, and for more information about some of the terms used below, see information about the acquired and innate immune systems.

Early inflammation
Inflammation is a response to any damage in the body and can be caused by infection, trauma, chemicals, heat or foreign, unrecognised particles (like pollen in hay fever). Inflammation is, above all, a protective response that aims to remove the cause of damage, as well as heal any damage that has already been caused. As mentioned before, inflammation is defined as redness, heat, pain and loss of function, and there are several stages to the process of inflammation that explain these. Firstly, the body tries to get as much blood as is possible to the damaged area. This is because there are lots of different substances in the blood that can help both to stop any further damage and also try and destroy the cause. These include both chemicals as well as lots of immune cells. So that this area can have as many good chemicals and immune cells as possible, the body dilates (makes wider) the blood vessels of the area allowing more blood to enter.
This increased blood flow is the reason that inflamed areas are hotter and redder than the surrounding area. After increasing the blood flow to the area, the body needs to get the chemicals and the immune cells out of the blood vessels and into the tissues. To do this, the cells that make up the blood vessels start to pull apart and create tiny holes in their walls. This allows very small molecules like water and some chemicals to escape into the tissues, while keeping larger molecules and cells on the inside. The fluid that leaks out, as well as the increased blood flow, is why the inflamed area appears swollen. These substances that are ‘leaking’ into the tissue from the blood vessels start to wall off the damaged area because it contains a substance called fibrin. Fibrin is a substance that makes up part of a scab, and can become hard. This helps in keeping the damaging substance isolated and stops it from spreading. Other chemicals that leak out into the tissues mean that the nerve fibres that transmit pain signals can become activated far more easily.
This is why inflamed areas are painful. Also because of all the leaking fluid, the blood flowing through this area starts to become thicker and moves more slowly through the area. This slowing down of blood makes the blood cells move differently, and they start travelling closer to the vessel walls that before. White blood cells from the immune system then make their way into the damaged tissue by attaching to the blood vessel walls. To help with this, the vessel walls in the inflamed area start to change the molecules on their surface meaning the white blood cells are more likely to attach. They can then move between tiny holes in the blood vessel wall and can migrate towards the area of inflammation following ‘trails’ of chemicals. These ‘trails’ can be bacterial products, inflammatory chemicals and immune signals.

Chemicals of inflammation
There are lots of chemicals and molecules that are involved in inflammation. Below is a brief list of some of the important ones:
Histamine
Histamine is a substance released mostly from cells called ‘mast cells’ that exist in the connective tissue of the body. When released, histamine causes the dilation of blood vessels and is an activator of most of the processes talked about above. Reasons for mast cells to release histamine include:

• Physical injury, heat or cold;
• Immune reactions with the antibody IgE (as in asthma);
• Activation by immune molecules (complement);
• Substances released from white blood cells.

Serotonin
Serotonin is a chemical responsible for dilating blood vessels in the body and is produced by cells called ‘endochromaffin’ cells within the gastrointestinal tract. In the brain, serotonin plays a role in regulating mood but this is very different than its role in the rest of the body.
Prostaglandins
Prostaglandins are produced through the action of an enzyme (a molecule that causes a chemical reaction) called cyclooxygenase. The two most common forms of this are known are COX-1 and COX-2 and these are essential for the inflammatory process. Prostaglandins also have a protective role in the gastrointestinal tract, preventing acid damage to the mucosa. The importance of this is that COX-1 and COX-2 are the chemicals inhibited by the use of most non-steroidal anti-inflammatories (NSAIDS) such as aspirin and ibuprofen. These block the production of prostaglandins and thus limit inflammation and pain but also slow the protective actions of prostaglandins. Drugs such as Vioxx and Celebrex block only the COX-2 enzyme and so allow this protective action to continue, although these drugs are associated with a moderate increase in the risk of heart attack.
Leukotrienes
Leukotrienes are responsible for activating white blood cells and causing them to attack foreign substances. Some leukotrienes are responsible for bronchospasm (closing of the airways) and so blockers of leukotrienes are sometimes used in the treatment of asthma.
TNF and IL-1
These two chemicals (Tumour Necrosis Factor and Interleukin-1) are responsible both for controlling a lot of processes involved in local inflammation as well as for a lot of the whole-body symptoms of inflammation such as:

• Fever;
• Loss of appetite;
• Different sleeping patterns;
• Release of white blood cells into the blood stream;
• Release of stress hormones.

Outcomes of early inflammation

Complete resolution
Complete resolution of acute inflammation is the ideal scenario, and involves the complete restoration in form and function to the inflamed area. It involves the removal of all the inflammatory chemicals, the return to normal blood flow, removal of white blood cells and removal of the excess tissue fluid.
 
Abscess formation
 
An abscess will form mostly in infections with bacteria that cause a lot of pus (a collection of dead cells, white cells and bacteria) to form.
 
Scarring (fibrosis)
 
This occurs after there has been either substantial tissue damage, when the inflammatory injury occurs in tissues that do not regenerate, or when there is excess fibrin exudation into tissues. If there is too much fibrin in the tissues, then connective tissue will grow into the area and covert it into a scar, rather than regrowing the normal tissue of the area.
 
Progression to chronic (long-term) inflammation
 
This may just be a very long version of the process described above, or may be a different and slow inflammatory process that has been ‘chronic’ for the course of the entire disease. 

Chronic (long-term) inflammation
In chronic inflammation, there is a different type of white blood cell called the macrophage that plays a key role. These macrophages can be activated by immune system, or by things such as bacterial toxins, bacteria themselves or foreign particles. These activated macrophages enlarge, become more active, and release large amounts of the chemical mediators detailed above. Chronic inflammation is characterised by having destructive processes as well as healing processes going on simultaneously, and new blood vessels form around these areas.
There are a few reasons that inflammations become long-term rather than short. Sometimes a foreign particle cannot be ‘seen’ by immune cells and so the response against it is much weaker than it would otherwise be. Even then, the substance cannot be broken down using the destructive chemicals and methods that the macrophage has and so the inflammation keeps going without end. Sometimes bacteria can cause the same thing, the classic example being tuberculosis. Sometimes, the body can even attack itself, in conditions like rheumatoid arthritis and systemic lupus erythematosus. In these diseases, inflammation is chronic because there will always be something for the body to attack, and the body will also be trying to heal these areas leading to a long inflammatory process.

What causes inflammation?

The most common cause of a relatively short period of inflammation is an infection, and almost all infections wither with bacteria, fungus or virus will cause inflammation. The red, sore throat of a cold is an example of inflammation secondary to a virus. As mentioned previously though, things such as physical trauma, toxins, heat, cold and allergic reactions also cause inflammation.
Below are some of the more common causes of chronic inflammation.

Persistent infections

• Syphilis;
• Certain fungi.

Prolonged exposure to potentially toxic agents

• Silicosis;
• Breathing in a lot of carbon (eg. coal miners);
• Atherosclerosis (plaque build-up on blood vessel walls).

Autoimmunity

• Rheumatoid arthritis;
• Systemic lupus erythematosus (SLE);
• Most other auto-immune conditions.

When to see a doctor about inflammation

Most inflammation will settle on its own as it is important to remember it is a completely natural process and part of the immune response. However, if inflammation is causing you difficulties with your daily activities, if it is causing you pain that you find uncomfortable or if you would like reassurance or advice then you should go and see your doctor. You should also see a doctor if there appears to be pus forming at the site of inflammation as this could be a sign of bacterial infection requiring antibiotics.

Tests for inflammation

There are some blood tests that your doctor may run to check for inflammation:

• CRP (C-Reactive Protein): CRP is a chemical, the levels of which rise dramatically when inflammation is occurring in the body. Measuring CRP can aid in determining disease progress and the effectiveness of treatment. CRP increases in hours of inflammation starting and falls within two to three days of recovery;
• ESR (Erythrocyte Sedimentation Rate): ESR is a non-specific indicator of the presence of disease. This is slower to show changes than CRP;
• FBP (Full Blood Picture): A Full Blood Picture can give the doctor an idea of the level of white blood cells that are in the blood. If there are more white blood cells than usual then this indicates infection.

Treatment of inflammation

Anti-inflammatory medications work through interruptions in the inflammatory pathways.

Steroidal anti-inflammatories
(Prednisolone, cortisol): These act by lowing both the inflammation and also immune responses of the body and are often used in conditions such as asthma and arthritis as well as inflammatory conditions of the joints where they can be directly injected into the inflamed area and cause a reduction in pain.
 
Non-steroidal anti-inflammatories
 
(NSAIDs): These work through the interruption of the cyclooxygenase pathway and so stop the production of prostaglandins which are vital in the inflammatory process. They also stop the good actions of prostaglandins though, and can result in things such as kidney problems and gastrointestinal ulceration. To lower these side-effects, COX-2 selective drugs are used which still have anti-inflammatory properties, but not as many of the side-effects. Unfortunately, these are linked to a moderately increased risk of heart disease and the risks and benefits of their use should be discussed with a doctor. Some NSAIDs are available as a topical application to reduce side-effects.
Types of NSAIDs include:

• Aspirin;
• Ibuprofen;
• Diclofenac (Voltaren);
• Celecoxib (COX-2 selective).

More recent anti-inflammatory agents can interrupt other areas in the pathway such as leukotriene blockers that are often used in asthma. There are also very modern and expensive agents that can be used in chronic inflammatory conditions that actually set the immune system of the body to attack inflammatory mediators such as TNF – these are very successful but currently prohibitively expensive and so are only used for very severe diseases.

References

1. Cotran RS, Kumar V, Collins S. Robbins Pathologic Basis of Disease. Philidelphia, W.B. Saunders Company, 1999.
2. Guyton AC, Hall JE. Textbook of Medical Physiology (Tenth Edition). Philadelphia, W.B Saunders Company, 2000.
3. Kearney PM, Baigent C, Godwin J, Halls H, et. al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ. 2006 Jun 3;332(7553):1302-8.
4. Kumar P, Clark M. Clinical Medicine (Sixth Edition). London, Elsevier, 2005.
5. Longmore M, Wilkinson IB, Rajagopalan S. Oxford Handbook of Clinical Medicine (Sixth Edition). New York, Oxford University Press, 2004.
6. Warren JS, Ward PA. The Inflammatory Response [online]. William’s Haematology, Access Medicine. Available at URL: http://www.accessmedicine.com (last accessed 12/09/06)

Drugs used in the treatment of inflammation:

• Brufen (Ibuprofen)
• Celebrex (Celecoxib)
• Diclofenac-BC (Diclofenac)
• GenRx Diclofenac (Diclofenac sodium)
• Mobic (Meloxicam)
• Naprosyn (Naproxen)
• Nurofen (Ibuprofen)
• Vioxx (no longer available) (Rofecoxib)
• Voltaren Rapid 12.5/ 25/ 50 (Diclofenac potassium)

Diseases presenting with inflammation include:

• Allergic Disease (An Introduction)
• Asthma
• Cholecystitis
• Crohn’s Disease (Inflammatory Bowel Disease)
• Croup (Viral laryngotracheobronchitis)
• Kawasaki Disease
• Lupus – Systemic Lupus Erythematosus (SLE)
• Osgood-Schlatter (OS) disease
• Pancreatitis (Acute)
• Psoriasis
• Syphilis
• Systemic Scleroderma (Systemic Sclerosis)
• Tennis elbow (lateral epicondylitis)
• Tuberculosis (TB)
• Ulcerative Colitis (Inflammatory Bowel Disease)
• Granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis)